Preparation of N-alkyl-N-pyridinyl-1H-indol-1-amines

ABSTRACT

The synthesis of memory enhancing, analgetic, and antidepressant N-alkyl-N-pyridinyl-1H-indol-1-amines is described.

This is a division of application Ser. No. 08/242,395 filed May 13, 1994now U.S. Pat. No 5,459,274 filed Oct. 17, 1995

The synthesis of memory enhancing, analgetic, and antidepressantN-alkyl-N-pyridinyl-1H-indol-1-amines 1, involving arylation of acompound of formula 2 ##STR1## by a halopyridine of formula 3 ##STR2##to provide an N-pyridinyl-1H-indol-1-amine of formula 4 ##STR3##followed by alkylation of 4 by a compound of formula 5

    R.sub.2 Z                                                  5

to yield an ultimate N-alkyl-N-pyridinyl-1H-indol-1-amine of formula 1##STR4## wherein R is hydrogen, loweralkyl or loweralkoxy; R₁ ishydrogen or loweralkyl; R₂ is loweralkyl; R₃ is hydrogen, loweralkyl orloweralkoxy; and m is 1 has been described. See, for example, U.S. Pat.No. 4,880,822 granted Nov. 14, 1989.

Applicants have now found that by starting with a 3-haloindole offormula 6 ##STR5## wherein R is as above and in addition istrifluoromethyl, R₁ is as above and m is as above and in addition is 2,prepared by halogenation of an indole of formula 7 ##STR6## wherein R(including trifluoromethyl), R₁ and m (including 2) are as above with ahalosuccinimide of formula 8 ##STR7## wherein X is bromo, chloro oriodo, aminating a 3-haloindole 6 to a 1-amino-3-haloindole 9 ##STR8##wherein R (including trifluoromethyl), R₁, X and m (including 2) are asabove, arylating a 1-aminoindole 9, so obtained, with a halopyridine 3wherein Y is a halogen to a 3-halo-N-pyridinylaminoindole 10 ##STR9##wherein R (including trifluoromethyl), R₁, R₃, X and m (including 2) areas above, alkylating an N-pyridinylaminoindole 10, so obtained, to anN-alkyl-3-halo-N-pyridinylaminoindole 11 ##STR10## wherein R (includingtrifluoromethyl), R₁, R₂, R₃, X and m (including 2) are as above, andfinally dehalogenating an N-alkyl-3-halo-N-pyridinylaminoindole 11, soobtained, an ultimate N-alkyl-N-pyridinyl-1H-indol-1-amine 1 wherein R(including trifluoromethyl), R₁, R₂, R₃ and m (including 2) are as aboveis obtained in high overall yield, even though halo group is introducedin the first step of the sequence and removed in the last step to formthe final product. In addition, costly, time consuming, yield reducingchromatographic separations and purifications are avoided in the presentprocess to prepare the desired pharmacological product.

Thus, the present invention relates to a process for the preparation ofmemory enhancing, analgetic and antidepressantN-alkyl-N-pyridinyl-1H-indole-1 -amines. More particularly, the presentinvention relates to a process for the preparation of memory enhancing,analgetic and antidepressant N-alkyl-N-pyridinyl-1H-indol- 1-amines offormula 1 involving the steps of halogenating a commercially availableor readily preparable indole 7 to a 3-haloindole 6, aminating a3-haloindole 6 to a 1-amino-3-haloindole 9, arylating a1-amino-3-haloindole 9 to a 3-halo-N-pyridinylaminoindole 10, alkylatinga 3-halo-N-pyridinylaminoindole 10 to anN-alkyl-3-halo-N-pyridinylaminoindole 11 and dehalogenating anN-alkyl-3-halo-N-pyridinylaminoindole 11 to anN-alkyl-N-pyridinylaminoindole 1, wherein R, R₁, R₂, X and M are asdescribed immediately above.

The present process is most particularly useful for the preparation ofN-alkyl-N-pyridinyl-1H-indole amines 1 wherein R is hydrogen; R₁ ishydrogen, R₂ is loweralkyl, R₃ is hydrogen and m is 1, and still mostparticularly wherein R₂ is n-propyl.

The halogenation of an indole 7 to a 3-haloindole 6 is accomplished bymethods known in the art, for example, by the use of anN-halosuccinimide 8 such as N-chlorosuccinamide in an aprotic dipolarsolvent, such as dimethylformamide at a reaction temperature of about10° to 18° C.

The amination is achieved by contacting a 3-haloindole 7 withhydroxylamine-0-sulfonic acid in a dipolar aprotic solvent in thepresence of a base or bases. Among dipolar aprotic solvents, there maybe mentioned dimethylacetamide, dimethylformamide,N-methyl-2-pyrrolidinone, dimethylsulfoxide and hexamethylphosphoramide,dimethylformamide being preferred. Among bases, there may be mentioned,alkali metal hydroxides and alkali metal carbonates, such as lithium,sodium and potassium hydroxides and lithium, sodium and potassiumcarbonates, respectively. Potassium hydroxide is the preferred base. Amixture of potassium hydroxide and potassium carbonate is the preferredmixture of bases. The amination reaction temperature is not narrowlycritical; the reaction proceeds at a satisfactory rate at a reducedtemperature of about -10° to about 20° C., an amination temperature ofabout 0° to about 10° being preferred.

The arylation is effected by contacting a 1-amino-3-haloindole 9 with ahalopyridine 3, as the free base or hydrohalide salt, preferably ahydrochloride salt, in a dipolar aprotic solvent such as, for example,dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, and N-methyl-2-pyrrolidinone, N-methyl-2-pyrrolidinonebeing preferred. The arylation proceeds at a reasonable rate at areaction temperature within the range of about 60° to 120° C., anarylation temperature of about 80° C. being preferred.

A 3-halo-N-pyridinylindolamine 10, is isolated as a benzoate salt,preferably the salicylate salt, prepared by treating a3-halo-N-pyridinylindolamine 10, with a benzoic acid, preferablysalicylic acid, in an alkyl alkanoate, preferably ethyl acetate, atambient temperature.

The alkylation is achieved by reacting a 3-halo-N-pyridinylindolamine10, with an alkyl halide 5, preferably an alkyl bromide, in a dipolaraprotic solvent (e.g., dimethylacetamide, dimethylformamide,dimethylsulfoxide, hexamethylphosphoramide, or N-methyl-2-pyrrolidinone)in the presence of a base (e.g., an alkali metal alkoxide, such as alithium, sodium or potassium alkoxide). Dimethylformamide is thepreferred solvent. Potassium tert-butoxide is the preferred base.

The alkylation is preferably performed at reduced temperatures withinthe range of about -10° to about 0° C. Alkylation temperatures withinthe range of about -20° to about 20° may be employed to effect theconversion.

When a benzoate salt of a 3-halo-N-pyridinylindolamine 10 is used in thealkylation step, the salt, preferably the salicylate salt, is convertedto the free base by treatment with an alkali metal hydroxide, such assodium hydroxide, in an aromatic solvent, such as toluene, by ordinarymethods.

An N-alkyl-3-halopyridinylindolamine 11 is isolated as a hydrohalidesalt, preferably the hydrochloride salt, prepared by treating anN-alkyl-3-halopyridinylindolamine 11 with a hydrogen halide, preferablyhydrogen chloride, in an ethereal solvent, preferably diethyl ether.

The final step of the sequence, the dehalogenation of anN-alkyl-3-halo-N-pyridinylindolamine 11 to a pharmacologically activeN-alkyl-N-pyridinylindolamine 1is accomplished by contacting anN-alkyl-3-halo-N-pyridinylindolamine 11 with formic acid in the presenceof a metal catalyst in an alkanol. Among alkanols, included aremethanol, ethanol, 1-and 2-propanols, 1,1-dimethylethanol and the like.2-Propanol is preferred. Included among metal catalysts arepalladium-on-carbon, Raney nickel, tetrakistriphenylphosphine palladium(0) and palladium acetate. Palladium-on-carbon is preferred.

The dehalogenation is carded out at elevated temperature, preferably thereflux temperature of the reaction medium, although it proceeds at areasonable rate at lower temperatures.

The dehalogenation may also be carried out on a hydrohalide salt,preferably the hydrochloride, of an N-alkyl-3-halo-N-pyridinylindolamine11. When a hydrohalide salt is used, a tertiary amine (e.g.,triethylamine, pyridine, picoline, lutidine, s-collidine, and the like)is employed to convert the salt to the free base.

An N-alkyl-N-pyridinylindolamine 11 is characterized as a hydrohalidesalt, preferably the hydrochloride salt, prepared by treating anindolamine 11 with a hydrohalic acid in an alkanol/ether, preferablymethanol/methyl tert-butyl ether, under ordinary conditions.

As used throughout the specification and appended claims, the term"alkyl" refers to a straight or branched chain hydrocarbon radicalcontaining no unsaturation and having 1 to 8 carbon atoms such asmethyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl,4-heptyl, 2-octyl, and the like; the term "alkanol" refers to a compoundformed by a combination of an alkyl group and a hydroxy radical.Examples of alkanols are methanol, ethanol, 1- and 2-propanol,1,1-dimethylethanol, hexanol, octanol and the like. The term "alkanoicacid" refers to a compound formed by combination of a carboxyl groupwith a hydrogen atom or alkyl group. Examples of alkanoic acids areformic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid,hexanoic acid, octanoic acid and the like; the term "halogen" refers toa member of the family consisting of chlorine, bromine, iodine andfluorine. The term "lower" as applied to any of the aforementionedgroups refers to a group having a carbon skeleton containing up to andincluding 6 carbon atoms.

The following examples are for illustrative purposes only and are not tobe construed as limiting the invention. All temperatures are given indegree centigrade (° C.).

EXAMPLE 1

Preparation of 3-chloroindole

To a 3 L round bottom flask equipped with a mechanical stirrer,thermometer and a Gooch tube was added sieve-dried dimethylformamide(1.2 L) and indole (200 g). The solution was stirred under an atmosphereof nitrogen and cooled to about 10° C. N-Chlorosuccinamide (216.6 g) wasadded via the Gooch tube at a rate such as to maintain a reactiontemperature of 10° -18° C. After the addition was complete, a secondcharge of N-chlorosuccinamide (34.2 g) was added. When the reaction wasfound to be >97% complete by high performance liquid chromatography, thereaction mixture was poured into a well-stirred, cold solution ofaqueous sodium bisulfite (5.2 L of 0.1% sodium bisulfite in water and640 g of ice). After about 15 min, the precipitate was collected andwashed with water (2×1 L). The filtrate was partitioned betweendichloromethane (1.3 L) and 0.1% aqueous sodium bisulfite solution (1L). The phases were separated and the aqueous solution was extractedwith dichloromethane (300 ml). The organic fractions were combined,washed with water (800 mL), dried over anhydrous magnesium sulfate,filtered and the filtrate was concentrated (at about 25° C. and about 50mm Hg). The residue was dried in a vacuum oven at 25° C. and about 125mm Hg for 2 to 4 hrs to yield 240.3 g (92.9%) of product, 3-chloroindole(91.6% pure).

EXAMPLE 2

Preparation of 3-chloro-1H-indol-1-amine To a 12 L round bottom flaskequipped with a mechanical stirrer, thermometer and a Gooch tube wasadded sieve-dried dimethylformamide (2.8 L), 3-chloroindole (240 g,91.6% pure), milled potassium carbonate (200.4 g), milled potassiumhydroxide (574.3 g, 85% pure) and dimethylformamide (900 mL) at -2° to5° C. The reaction mixture was cooled to about 0° C. andhydroxylamine-O-sulfonic acid (338.2 g, 97% pure) was added portionwisevia the Gooch tube over a period of about 4 hrs, maintaining thereaction temperature at about 0° C. When the reaction was >95% complete(by high performance liquid chromatography), the reaction mixture waspoured into a well-stirred, cold mixture of water (18 L and 3.6 kg ice)and toluene (2.4 L). After about 5 mins, the phases were separated andthe aqueous phase was extracted with toluene (1×2.4 L and 1×1 L). Theorganic fractions were combined and filtered through Celite. Thefiltrate was concentrated under reduced pressure (about 50 mm Hg) atabout 60° C. to yield 245 g (86%) of product.

EXAMPLE 3

Preparation of 3-chloro-N-4-pyridinyl-1H-indol-1-amine salicylate

A mixture of 3-chloro-1H-indol-1 -amine (100 g),1-methyl-2-pyrrolidinone (490 mL) and 4-chloropyridine hydrochloride(75.9 g, 96.2% pure) was heated at about 80° C., with stirring, undernitrogen, for 2 hrs. When the reaction was 88-89% complete, the reactionmixture was cooled to room temperature and poured into a well-stirredmixture of 5% sodium hydroxide solution (1.2 L) and toluene (800 mL).The mixture was stirred for 15 mins, filtered through Celite, and thephases of the filtrate were separated. The aqueous phase was extractedwith toluene (1×400 mL and 1×200 mL). The organic fractions werecombined and washed with water (800 mL). The emulsion was filteredthrough Celite and the phases were separated. The organic phase wasdried over anhydrous potassium carbonate, filtered and the filtrate wasconcentrated at 50°-60° C. under reduced pressure (about 50 mm Hg) toprovide 131.5 g of product as the free base.

The product, 3-chloro-N-4-pyridinyl-1H-indol-1-amine, was dissolved inethyl acetate (745 mL) and filtered. The filtrate was added to a 2 Lround bottom flask equipped with a mechanical stirrer. Salicylic acid(80.7 g) was added, with stirring, under a nitrogen atmosphere at roomtemperature. After stirring the mixture at room temperature for 2 hrs,the precipitate was collected and the filter cake was washed with cold(0°-5° C.) ethyl acetate (30 mL) and dried at 68°-70° C. (125 mm Hg) for16 hrs to give 90.0 g (48.4%) of product,3-chloro-N-4-pyridinyl-1H-indol-1-amine salicylate (99% pure), mp of185°-186° C.

EXAMPLE 4

Preparation of 3-chloro-N-propyl-N-4-pyridinyl-1H-indol-1-aminehydrochloride

A solution of 3-chloro-N-4-pyridinyl-1H-indol-1-amine salicylate (10 g),toluene (100 mL) and 5% aqueous sodium hydroxide solution (100 mL) wasfiltered through Celite and the phases were separated. The aqueous phasewas extracted with toluene (50 mL), and the combined organic phase waswashed with water (75 mL), dried over anhydrous potassium carbonate,filtered and the filtrate was concentrated (50° C. bath, 50 mm Hg) togive the free base, 3-chloro-N-4-pyridinyl-1H-indol-1-amine.

To a 125 mL round bottom flask equipped with a mechanical stirrer,thermometer and a Gooch tube was added sieve-dried dimethylformamide (36mL) and 3-chloro-N-4-pyridinyl-1H-indol-1-amine (4.5 g). The solutionwas cooled to about --10° C., with stirring, under a nitrogenatmosphere. Potassium-τ-butoxide (2.29 g) was added via the Gooch tubeat a rate such as to maintain a reaction temperature of about -10° C.After the addition was complete, the mixture was allowed to warm toabout 0° C. and age for about 1 hr. The Gooch tube was replaced with adropping funnel and a solution of 1-bromopropane (2.96 g) in drydimethylformamide (8.8 mL) was added at a rare such as to maintain areaction temperature of about 0° C. When the reaction was 98% complete,the reaction mixture was poured into a stirred mixture of cold water (72mL) and ethyl acetate (30 mL). The phases were separated and the aqueousphase was extracted with ethyl acetate (2×30 mL). The combined organicphase was washed with water (50 mL), dried over anhydrous magnesiumsulfate, filtered and the filtrate was concentrated (at about 40° C.bath temperature and about 50 mm Hg) to yield 5.1 g (96.2%) of productas the free base (88.6% pure).

To a 4 g sample of product, 3-chloro-N-propyl-N-4-pyridinyl-1H-indol- 1-amine, dissolved in anhydrous ether (60 mL) in a 125 mL-round bottomflask equipped with a mechanical stirrer, thermometer and droppingfunnel, was added slowly an ethereal solution saturated with hydrogenchloride (6 mL) at room temperature, under a nitrogen atmosphere, withstirring. After about 0.5 hrs at room temperature, the precipitate wascollected, washed with anhydrous ether (15 mL) and dried to yield 3.95 g(87.6%) of product.

EXAMPLE 5

Preparation of N-propyl-N-4-pyridinyl-1H-indol-1amine hydrochloride

To a mixture of 3-chloro-N-propyl-N-4-pyridinyl-1H-indol- 1 -aminehydrochloride (500 mg), triethylamine (408 mg) and 5%palladium-on-carbon (34.7 mg) in 2-propanol (2.5 mL) was added, under anitrogen purge, 98% formic acid (0.068 mL) via a syringe, with stirring.After the addition was complete, the reaction mixture was heated toreflux. Additional amounts of 5% palladium-on-carbon (104 mg),triethylamine (0.22 mL) and formic acid (0.028 mL) were added over 7.5hrs in 3 portions. The mixture was cooled to room temperature, filteredthrough Celite and the filter cake was washed with 2-propanol (about 30mL). The filtrate was concentrated under reduced pressure (50 mm Hg) andthe residue partitioned between toluene (8 mL) and 5% aqueous sodiumhydroxide solution (8 mL). The aqueous phase was separated and extractedwith toluene (5 mL). The organic fractions were combined, washed withwater (10 mL), dried over anhydrous magnesium sulfate and filtered. Thefiltrate was concentrated under reduced pressure (50 mm Hg) at 60° C. toyield 310 mg (79.5%) of the product, as the free base, (99% pure).

To a 25 mL round bottom flask equipped with a mechanical stirrer,thermometer and condenser was addedN-propyl-N-4-pyridinyl-1H-indol-1amine (2.1 g), methanol (2 mL), and36-37% hydrochloric acid (0.66 mL), with stirring, at room temperature.The reaction mixture was seeded with product prepared previously and,after 5 mins, methyl-t-butyl ether (8.0 mL) was added, with stirring.The reaction mixture was allowed to cool to room temperature, thencooled to about 0° C. The precipitate was collected and the filter cakewas washed with cold 1:4 methanol/methyl-t-butyl ether (2 mL), followedby methyl-t-butyl ether (6 mL) and dried at 85° C. (25 inches ofmercury) to yield 2.07 g (88.6%) of product.

The determination of the purity of the reactants and the products of theexamples was determined in a Perkin-Elmer 410/Kratos Spectroflow 783high performance liquid chromatograph using a Phenomenex Bondclone 10C18(3.9×300 mm) column with a mobile phase of 50:50 acetonitrile/0.1Naqueous ammonium formate solution at a flow rate of 1.5 mL/min. withdetection at 255 nm. Samples were prepared in acetonitrile, filtered andapplied to the column.

We claim:
 1. A process for the preparation of a compound of the formulawith high purity ##STR11## wherein R is hydrogen, loweralkyl,loweralkoxy or trifluoromethyl; R₁ is hydrogen or loweralkyl; R₂ isloweralkyl; R₃ is hydrogen, loweralkyl, loweralkoxy or trifluoromethyl;and m is 1 or 2 which comprises the steps of:(a) contacting a compoundof the formula ##STR12## wherein R, R₁, R₂, R₃, and m are as above and Xis bromo or chloro with formic acid in the presence of a metal catalystin reflex temperature with 2-propanol; and (b) isolating the product. 2.A process according to claim 1 wherein the metal catalyst is selectedfrom the group consisting of palladium-on-carbon, Raney nickel,tetrakistriphenylphosphine palladium (0), and palladium acetate.
 3. Theprocess according to claim 2 wherein the palladium-on-carbon is 5%palladium-on-carbon.
 4. A process according to claim 1 wherein ahydrohalide salt of a compound of step (a) is employed.
 5. The processaccording to claim 4 wherein the hydrohalide salt is the hydrochloridesalt.
 6. A process according to claim 1 wherein a base is employed whena hydrohalide salt of the compound of step (a) is used.
 7. A processaccording to claim 6 wherein the base is a tertiary amine.
 8. Theprocess according to claim 7 wherein the tertiary amine istriethylamine.
 9. The process according to claim 6 wherein thehydrohalide salt is the hydrochloride salt.
 10. A process according toclaim 1 wherein the product is treated with a hydrohalic acid in analkanol to form a hydrohalide salt thereof.
 11. The process according toclaim 10 wherein the hydrohalic acid is hydrochloric acid.
 12. Theprocess according to claim 10 wherein the alkanol is methanol.